Steroidal 6-cyclopropyl-4-en-3-ones and process for preparing same



United States Patent 3,463,776 STEROIDAL 6-CYCLOPROPYL-4-EN-3-ONES ANDPROCESS FOR PREPARING SAME Michael GeorgeLester, Oliver Stephenson, andVladimir Petrow, London, England, assignors to The British Drug HousesLimited No Drawing. Filed Sept. 9, 1966, Ser. No. 578,154 Claimspriority, application Great Britain, Sept. 23, 1965, 40,556/ 65 Int. Cl.C07c 173/00, 169/36; A61k 17/00 US. Cl. 260-23957 3 Claims ABSTRACT OFTHE DISCLOSURE Steroidal 6-cyclopropyl-4-en-3-ones having usefulbiological properties are prepared by reacting steroidal 6-methylene-4-en-3-ones with a dialykyl or diarylsulphoxonium methylide inan anhydrous unreactive solvent medium.

This invention is for improvements in or relating to organic compounds,and has particular reference to a class of steroidal materials, namely6-cyclopropyl-4-en-3- ones.

It is an object of the present invention to provide certain steroidal6-cyclopropyl-4-en-3-ones, which compounds are of value on account oftheir biological properties. Thus, the compounds of the presentinvention may possess anabolic, androgenic, claudogenic, progestational,anti-endotoxic or anti-inflammatory properties, which render them ofvalue for therapeutic or veterinary use. In addition, the compounds ofthe present invention have great utility as intermediates for thepreparation of compounds with valuable biological properties.

The invention provides the following new compounds:17fl-acetoxy-6-cyclopropyl-1'9-morandrost 4 en-3-one, which has anabolicand claudogenic proper-ties.

6-cyclopropyl-16a,17a isopropylidenedioxypregn 4- en-3-one, which hasanti-infiammatory and progestational properties.

17,8-acetoxy-6-cyclopropyl 16 methylenepregn-4-ene- 3,20-dione, whichhas progestational, anti-endotoxic, antiinflammatory and an'ti-ovulatoryproperties. It is also of interest in experimental tumor chemotherapy.

fi-cyclopropyl-l7u-acetoxypregn 4 ene3,20-dione, which hasprogestational, anti-ovulatory and gonadotrophin-inhibiting properties.

170:, 20:20,2l-bismethylenedioxy 6 cyclopropylpregn-4-ene-3,l1-dione,which may be converted by methods of prior art into the correspondingcorticoid which has biological properties associated with cortisone.

6-cyc1opropyl-17a,20a-dihydroxy 20/3 methyl 3- oxopregn-4-ena2l-oic acid-lactone and I 6-cyclopropyl-17a-hydroxy-20-methyl 3 oxypregna-4,20-dien-21-oic acid y-lactone, which have antibiotic properties.

According to the present invention there is provided a process for thepreparation of steroidal 6-cyclopropyl-4- en-3-ones of theD-hornoandrostane, 19-norandrostane, pregnane, l9-norpregnane andD-homopregnane series of partial formula (I):

A B A B i; Ha

I II

which process comprises reacting a corresponding steroidal6-mehylene-4-en-3-one of partial Formula II with carbene.

The carbene is preferably generated in situ from a dialkylordiarysulphoxonium methylide.

In carrying the process of the invention into effect the6-rnethylene-4-en-3-one (ll) either in the solid state or in a suitablesolvent, such for example as a lower ether, tetrahydrofuran, dioxan,dimethyl sulphoxide, dimethylformamide or a halogenated hydrocarbon, maybe reacted preferably in an inert atmosphere with a solution containing1 or more equivalents of a dialkylor diarylsulphoxonium methylide,preferably dimethylsulphoxonium methylide. The dialkyl ordiarylsulphoxonium methylide may be prepared by reacting a dialkyl ordiarylmethylsulphoxonium halide preferably trimethylsulphoxonium iodideor chloride in a suitable solvent for example dimethyl sulphoxide,tetrahydrofuran or dioxan preferably in the presence of an inertatmosphere with a base such for example as a metal hydride, a metalalkyl or aryl or a metal amide. In a preferred embodiment of theinvention, the reaction of the steroid with the methylide reagent iscarried out at room temperature. Stirring may be desirable especiallywhere the reaction mixture is not homogeneous. The reaction is normallycomplete within 4 hours but longer reaction times are not detrimental tothe process of the invention. Thereafter the prodnets of the reactionmay be isolated, for example by diluting the mixture with water andcollecting the separated solids by filtration or if desired, followingdilution with water, the mixture may be extracted with a suitablewater-immiscible solvent. The products may then be purified by standardtechniques.

The process of the invention may be applied to 6- methylene-3-oxo-A-steroids derived from D-homoandrostane, 19-normandrostane, pregnane,19-norpregnane, D- homopregnane, cholestane, spirostane, ergostane andstigmastane.

Methods for the preparation of 6-methylene-3-oxo-A steroids used asstarting materials for the process of the present invention have beendescribed by Burn, Cooley, Davies, Ducker, Ellis, Feather, 'I-Iiscock,Kirk, Leftwick,

Petrow and Williamson, Tetrahedron, 1964, 20, 597.

The following additional groups will not, in general, interfere with theprocess of the invention.

Hydroxy or acyloxy groups in various positions in the steroid molecule.A Nor-acyloxy group, however, when in conjunction with a 20-oxo-functionmay undergo internal condensation to form a -lactone during the processof the invention but, if desired, this condensation may be pre vented byprior protection of the 20-ox0 group by conversion into, for example, aketal derivative. Alternatively, the required l7tx-acyloxy group may besubsequently generated from a l7a-hydroxy group which, when inconjunction with a 20-oxo-function is unaflected by the process of theinvention.

Groups formed by condensation of 20-ketopregnane- 1'6oc,17oc-g1yCO1Swith carbonylic components such as acetone.

Carbonyl groups at C C C C C C and C Such groups however may undergoconversion to oxiranes during the process of the invention but may beprotected by prior conversion into, for example, ketal derivatives, andsubsequently regenerated is so desired.

Carbalkoxy groups at C C C C or in the side chain.

Alkyl groups and in particular methyl groups at C 2 11 C16, 17, C18, 19,21 and ethyl at 1?- Alkenyl and alkynyl groups, in particular vinyl andallyl, trifluoropropynyl, trifluorovinyl, ethynyl, propynyl, chloroandbromo-ethynyl at C Methylene, halomethylene and ethylidene groups at C Cand C methylene, halo and carboxymethylene bridging C16 and C17-Lactone, ether and spiroketal residues. Spirolactone residues such asO.CO.CH .CH attached to C etheric groups at C and bridging C and Cspiroketal moieties such as are present in diosgenin.

Halogen groups and in particular chlorine and fluorine at C C C and Cand halomethyl at C Isolated unsaturated linkages, in particular at C 1114 C16 and 17(20)- Cortical side-chain converted into such protectedderivatives as bismethylenedioxy. The free cortical side-chain may besubsequently regenerated if desired by methods well known to thoseskilled in the art.

Epoxides, particularly at C Additional cyclic structures on ring D andin particular the cyclic structure as described in United States PatentNo. 3,265,717.

The process of the invention may be applied to the 6- methylenederivatives of the following steroidal 3-oxo-4- enes:

l9-nortestosterone Z-methyl-19-nortestosterone17u-methyl-19-nortestosterone 9 11)-dehydro-l7a-methyl-19-nortest0sterone 17a-propynyl-,l7u-chlorethynyl-, 17 ot-trifluoropropynyl,

l7a-trifluorovinyl-19-nortesterone 17u-acyloxyprogesterones and 19-norderivatives thereof 9 1 1)-dehydro-17a-acyloxyprogesterones16-methyl-17a-acyloxyprogesterones,16-halomethyl-17aacyloxyprogesterones 9 1 1)-dehydro-16-methyl-17a-acyloxyprogesterones16-methylene-17u-acyloxyprogesterones,16-halomethylene-17u-acyloxyprogesterones 9 l 1 -dehydro-16-methylene-17 u-acyloxyprogesterones 17m-acyloxy-16-ethylideneprogesterones16a,17a-dimethylmethylenedioxyproge-sterone 9 1 1-dehydro-16m,17a-dimethylmethylenedioxyprogesterone cortisone16-methylcortisone, 16-halomethylcortisone and the 21- fiuoroderivatives thereof 21methylcortisone and the 21-fluoro derivativesthereof 16-methylenecortisone, 16-halomethylenecortisone and the21-fluoro derivatives thereof 16a-hydroxy cortisone and the(16a,17a)-acetonide thereof hydrocortisone 16-methylhydrocortisone,16-halomethylhydrocortisone and the 21-fluoro derivatives thereof21-methylhydrocortisone and the 21-fiuoro derivatives thereof16-methylenehydrocortisone, 16-halomethy1enehydrocortisone and the21-fluor0 derivatives thereof 16a-hydroxyhydrocortisone and the(16a,17oc)-aC6t0ni(le thereof17a,21-dihydroxypregna-4,9(11)-diene-3,20-dione16-methyl-17a,21-dihydr0xypregna-4,9( 1 1)-diene-3,20-

dione 21-methyl-17a,21-dihydroxypregna-4,9 (1 1 -diene-3,20-

dione 16-methylene-17a,21-dihydroxypregna-4,9(11)-diene- 3,20-dione16u-hydroxy-170,21-dihydroxypregna-4,9 l l -dicne- 3,20-dione and the(16,17)-acetonide thereof21-fluoro-16u,17a-dihydroxypregna-4,9(11)-diene-3,20-

dione and the (16,17) -acetonide thereof21-fluoro-16u,17a-dihydroxypregna-4-ene-3 ,1 1,20-trione and the(16,17)-acetonide thereof 21-fluoro-1 1,16a,17a-trihydroxypregn-4-ene-3,20-dione and the (16,17)-acetonide thereof 21-hydroxypregna-4,l7-dien-3-one 11-oxo-2l-hydr0xypregna-4,17-dien-3-one 11,21-dihydroxypregna-4,17-dien-3-one9(11)-dehydro-21-hydroxypregna-4,17-dien-3-one 3-oxopregna-4-17-dien-21-oic acid (esters) 3,1l-dioxopregna-4,17-dien-21-0ic acid (esters)11-hydroxy-3-oxopregna-4,17-dien-21-oic acid (esters) 9( 11)-dehydro-3-oxopregna-4,17-dien-21-oic acid (esters) 2 l-fluoro-17a-acy1oxyprogester0nes progesterone 16-methylprogester0nell-oxoprogesterone 9(11)-dehydroprogesterone 2 1 -methylprogesteronediosgenone 16 a and 8) -hydroxy-19-nortestosterone 16-methyl-1 6, 1 7-dehydro progesterone lfi-cyano-progesterone 16-carbalkoxyprogesterones16-hydroxymethylprogesterone 3-(3-oxo-178-hydroxyandrost-4-en-17a-yl)pr0pionic acid 21-flu0roprogesteronetestololactone 17m-ethylprogesterone11B-hydroxypentara-4,17(20)-diene-3,21dione The 9u-fluoro derivatives ofthe above 11 fl-hydroxy and 1 1oxo-steroids Following is a descriptionby way of example of methods of carrying the invention into effect.

EXAMPLE 1 17,8-acetoxy-6-cyclopropyl-19-norandrost-4-ene-3 one17fi-acetoxy-6-methylene-19-norandrost 4 en 3 one (0.75 g.) was added toa solution of dimethylsulphoxonium methylide, prepared under nitrogen atroom temperature by stirring trimethylsulphoxonium iodide (0.6 g.) indimethyl sulphoxide (8 ml.) with a 50% dispersion in oil of sodiumhydride (0.12 g.) until evolution of hydrogen had ceased. The mixturewas allowed to stand at room temperature under nitrogen for 3 /2 hoursand was then poured with stirring into 200 ml. of water. Theprecipitated solid was collected by filtration under suction, washedwith water and dried in the air. The crude solid was then dissolved inan ethyl acetate/ether/petroleum ether (B.P. 6080) mixture (5 :5 :2 byvol.) and chromatographed on alumina. Elution with this solvent mixturegave a colourless gum which was crystallised by dissolution in 3 m1. ofcyclohexane and allowing the mixture to stand at 0 C. overnight.Recrystallisation from petroleum ether (RP. 60-- aflorded17B-acetoxy-6-cyclopropyl-19-norandrost-4- cn-3-one, M.P. 107.5 G, A 248my (e, 14,700), [u] {153 (in CHCI EXAMPLE 2 (IJOMe Me 16a,17aisopropylidenedioxy-6-methylenepregn-4-ene- 3,20dione (1.5 g.) in drydioxan (15 ml.) was added to a solution of dimethylsulphoxoniummethylide, prepared under nitrogen at room temperature by stirringtrimethylsulphoxonium iodide (1.0 g.) in dimethyl sulphoxide (15 ml.)with a 50% dispersion in oil of sodium hydride (0.2 g.) until evolutionof hydrogen had ceased (1020 minmites). The mixture was allowed to standat room temperature under nitrogen for 4 hours and was then poured withstirring into 250 ml. of water. The precipitated solid was collected bysuction'filtration, washed with water and dried on the steam bath.Crystallisation from ethanol gave 6-cyc1opropyl 16a,17aisopropylidenedioxypregn- 4-ene-3,20-dione, M.P. 181 C., x 248 my. (e14,400), [m1 231 (in CHCIg).

EXAMPLE 3 17a-acetoxy-fi-cyclopropyl-16-methylenepregn-4-en- 3 ,20-dione17a-acetoxy-6,lG-dimethylenepregn 4 en-3,20-dione (1.0 g.) in ml. drytetrahydrofuran was added at room temperature to a solution ofdimethylsulphoxonium methylide, prepared under nitrogen by heating for 4hours under reflux with stirring a mixture of trimethylsulphoxoniumchloride (0.77 g.) and a 50% dispersion in oil of sodium hydride (0.15g.) in dry tetrahydrofuran (10 ml.). The mixture was allowed to stand atroom temperature under nitrogen for 8 hours. It was then poured into 200m1. of water with stirring, and the crude product was extracted withethyl acetate (2X50 ml.). The combined extracts were washed with water,dried and evaporated to give a residue which was crystallised fromaqueous ethanol to give 17a-acetoxy-G-cyclopropyl-16-methylenepregn-4-en-3,20-dione, M.P. 187.5 C., A 248 my. (6, 14,700),[ab-+67" (in CHCl EXAMPLE 46-cyclopropy1-17a-acetoxypregn-4-en-3,20-dione COMe17a-hydroxy-6-methylenepregn-4'en-3,20-dione (1 g.) was added to asolution of dimethylsulphoxonium methylide, prepared under nitrogen atroom temperature by stirring trimethylsulphoxonium iodide (0.7 g.) indimethyl sulphoxide 10 ml.) with a 50% dispersion in oil of sodiumhydride. (0.14 g.) until evolution of hydrogen had ceased. The mixturewas allowed to stand at room temperature under nitrogen for 3 hours andwas then poured with stirring into 200 ml. of water. The precipitatedsolid was collected by suction filtration, Washed with water and driedon the steambath. crystallisation from acetone/petroleum ether (B.P. 60afforded 6-cyclopropyl-l7a-hydroxypregn-4-en-3,20-dione, M.P. 228 C.,[ab 203 (in CHCI A 248.5 m (e 14,400).

On refluxing 8 hours in acetic anhydride was obtained17m-acetoxy-6-cyclopropylpregn 4 en-3,20-dione, M.P. 223 C., A 249 m,(6, 13,300) [a] +188 (in CHCI EXAMPLE 5 1711,20:20,21-bismethylenedioxy6 methylenepregn- 4-ene-3,11-dione (0.9 g.) was added to a solution ofdimethylsulphoxonium methylide, prepared under nitrogen at roomtemperature by stirring trime'thylsulphoxonium iodide (0.6 g.) indimethyl sulphoxide (10 ml.) with a 50% dispersion in oil of sodiumhydride (0.12 g.) until evolution of hydrogen had ceased. The mixturewas alloyed to stand at room temperature under nitrogen for 3 hours andwas then poured into 200 ml. of water. The solid which separated wascollected by suction filtration, washed with water and dried on thesteambath. Crystallisation from ethyl acetate gave 17a,20120,21bismethylenedioxy-6-cyclopropylpregn 4 ene-3,11-dione, M.P. 235 C., x247 m, (6 13,500), [a] 152 (in CHC13).

EXAMPLE 66-cyclopropyl-17a,20u-dihydroxy-20B-methyl-3-oxopregn-4-en-21-oic acid'y-lactone Me 0:0 6Q

EXAMPLE 7 6-cyclopropyl-l7a-hydroxy-20-methyl-3-oxopregna-4,20-clien-21-oic acid 'y-lactone From another fraction from thechromatographic procedure described in Example 6 was obtained aftercrystallisation from acetone 6 cyclopropyl 17a hydroxy 20- methyl 3oxopregna 4,20 dien 21 oic acid 7- lactone, rn.p. 260 C., k 224 m (617,200) and 242 III/.0 (e 14,600).

We claim:

1. 17a acetoxy 6 cyclopropyl 16 methylenepregn-4-ene-3,20-dione.

2. 6 cyclopropyl 17a,20a dihydroxy 20p methyl- 3-oXopregn-4-en-2l-0icacid 'y-lactone.

3. 6 cyclopropyl 17a hydroxy 20 methyl 3- oXopregna-4,20-dien-21-oicacid y-lactone.

References Cited UNITED STATES PATENTS 7/1966 Colton et al. 260-239.53/1968 Georgian et al. 260239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 260239.55, 397.4, 999

